Nociceptin (the same substance as orphanin FQ) is a peptide comprising 17 amino acid units having a similar structure to that of opioid peptide. Nociceptin has an augmenting activity on reaction against nociceptive stimulation, an appetite stimulating activity, an activity for reducing a space learning ability, an antagonism against an analgesic action of classic opiate agonists, a dopamine release inhibitory action, a water diuresis action, a vasodilative action and a systemic blood pressure-lowering action, and it is considered to take part in intracerebral controlling of pain, appetite and memory learning through a nociceptin receptor ORL1 [cf. Nature, 377, 532 (1995); Society for Neuroscience, 22, 455 (1996); NeuroReport, 8, 423 (1997); Eur. J. Neuroscience, 9, 194 (1997); Neuroscience, 75, 1 (1996); ibid., 333; Life Sciences, 60, PL15 (1997); ibid., PL141; Proceedings for National Academy of Sciences, 94, 14858 (1997)].
Further, it is known that morphine tolerance is reduced or memory and learning ability are improved in knockout mice in which expression of nociceptin receptor ORL1 is inhibited [cf. Neuroscience Letters, 237, 136 (1997)]; Nature, 394, 577 (1998)].
It has also been reported that nociceptin itself induces symptoms resembling withdrawal symptoms observed with morphine addicts, and that non-peptide nociceptin receptor antagonist improves morphine tolerance, dependence and symptoms resembling withdrawal symptoms [cf. Psychopharmacology, 151, 344–350 (2000); Journal of Neuroscience, 20, 7640 (2000)].
On the other hand, nociceptin protein precursor-defective mice are reported to show behaviors resembling anxiety and changes in stress response [cf Proceedings for National Academy of Sciences, 96, 10444 (1999)].
Hence the substances which specifically inhibit binding of nociceptin to nociceptin receptor ORL1 are useful as an analgesic against diseases accompanied with pain such as cancerous pain, postoperative pain, migraine, gout, chronic rheumatism, chronic pain and neuralgia; a reliever against tolerance to narcotic analgesic represented by morphine; a reliever against dependence on narcotic analgesic represented by morphine or against addiction; an analgesic enhancer; an antiobestic or appetite suppressor; a treating or prophylactic agent for cognitive impairment and dementia/amnesia in aging, cerebrovascular diseases and Alzheimer's disease; an agent for treating developmental cognitive abnormality in attention deficit, hyperactivity disorder and learning disability; a remedy for schizophrenia; an agent for treating neurodegenerative diseases represented by Parkinsonism and chorea; an anti-depressant or treating agent for affective disorder; a treating or prophylactic agent for diabetes insipidus; a treating or prophylactic agent for polyuria; a remedy for hypotension, and the like.
Substances which specifically inhibit binding of nociceptin to nociceptin receptor ORL1 are described, for example, in International Publications WO99/36421A, WO99/59997A, WO00/14067A and WO00/27815A; EPO Publications EP963987A2 and EP970957A1. None of these, however, relates to compounds having a benzimidazole ring.
Furthermore, EP 0254322 and EP 0370381 disclosed compounds resembling benzimidazole derivatives of the present invention, but none of the compounds disclosed in these publications has 1) a specific aliphatic carbonyl group or alicyclic amido group at 2-position of benzimidazole skeletal structure and/or 2) a nitrogen-containing heterocyclic ring at 6-position of said structure. They clearly differ from the compounds of the present invention.